EP1924560B1 - 6-substituierte- 2,3,4,5-tetrahydro-1h-benzo[d]azepine als 5-ht2c-rezeptoragonisten - Google Patents

6-substituierte- 2,3,4,5-tetrahydro-1h-benzo[d]azepine als 5-ht2c-rezeptoragonisten Download PDF

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EP1924560B1
EP1924560B1 EP06802858A EP06802858A EP1924560B1 EP 1924560 B1 EP1924560 B1 EP 1924560B1 EP 06802858 A EP06802858 A EP 06802858A EP 06802858 A EP06802858 A EP 06802858A EP 1924560 B1 EP1924560 B1 EP 1924560B1
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alkyl
optionally substituted
substituents
fluoro substituents
cycloalkyl
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EP1924560A1 (de
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John Gordon Allen
Karin Briner
Christopher Stanley Galka
Richard Charles Hoying
Maria Angeles Martinez-Grau
Julie Miyashiro
Natalia Pokrovskaia
Matthew Robert Reinhard
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Eli Lilly and Co
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Eli Lilly and Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has a rich pharmacology arising from a heterogeneous population of at least seven receptor classes.
  • the serotonin 5-HT 2 class is further subdivided into at least three subtypes, designated 5-HT 2A , 5-HT 2B , and 5-HT 2C .
  • the 5-HT 2C receptor has been isolated and characterized ( Julius, et al., U.S. Patent No. 4,985,352 ), and transgenic mice lacking the 5-HT 2C receptor have been reported to exhibit seizures and an eating disorder resulting in increased consumption of food ( Julius et al., U.S. Patent No. 5,698,766 ).
  • the 5-HT 2C receptor has also been linked to various other neurological disorders including obesity ( Vickers et al., Psychopharmacology, 167: 274-280 (2003 )), hyperphagia ( Tecott et al., Nature, 374: 542-546 (1995 )), obsessive compulsive disorder ( Martin et al., Pharmacol. Biochem. Behav., 71: 615 (2002 ); Chou-Green et al., Physiology & Behavior, 78: 641-649 (2003 )), depression ( Leysen159, Kelder, Trends in Drug Research II, 29: 49-61 (1998 )), anxiety ( Curr. Opin. Invest. Drugs 2(4), p.
  • the present invention provides selective 5-HT 2C agonist compounds of Formula I: where: R 6 is -(C 1 -C 3 )alkyl-S-(C 0 -C 3 )alkyl-R 10 , -(C 1 -C 3 )alkyl-NR 12 -(C 0 -C 3 )alkyl-R 11 , or -(C 1 -C 3 )alkyl-O-(C 0 -C 3 )alkyl-R 13 ; R 10 is -(C 1 -C 3 )alkyl-S-(C 0 -C 3 )alkyl-R 10 , -(C 1 -C 3 )alkyl-NR 12 -(C 0 -C 3 )alkyl-R 11 , or -(C 1 -C 3 )alkyl-O-(C 0 -C 3 )alkyl-R 13 ; R 10 is -(C 1 -C 3 )
  • Ar 1 is pyridyl, optionally substituted with 1 to 4 independently selected halo substituents, or with 1 to 3 substituents independently selected from the group consisting of halo, cyano, hydroxy, acetyl, methyl, -CF 3 , methoxy, -OCF 3 , methylthio, -SCF 3 ;
  • Ph 1 is phenyl optionally substituted with 1 to 5 independently selected halo substituents, or with 1 to 3 substituents independently selected from the group consisting of halo, cyano, hydroxy, acetyl, methylthio, -SCF 3 , (C 1 -C 6 )alkyl optionally further substituted with 1 to 6 fluoro substituents, and (C 1 -C 6 )alkoxy optionally further substituted with 1 to 6 fluoro substituents;
  • Het 1 is a saturated, nitrogen-containing heterocycle substituent selected from the group consisting of pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, and homothiomorpholinyl, any of which may optionally be substituted with (C 1 -C 6 )alkyl or with 2 methyl substituents; or a pharmaceutically acceptable salt or solvate thereof.
  • compositions which comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, diluent, or excipient.
  • the present invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating obsessive/compulsive disorder.
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating depression.
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating anxiety.
  • a compound of Formula I for use in the treatment of obesity, hyperphagia, obsessive/compulsive disorder, depression, anxiety, substance abuse, sleep disorder, hot flashes, and/or hypogonadism.
  • Particularly preferred embodiments of this aspect of the invention include the treatment of obesity, obsessive/compulsive disorder, depression, and/or anxiety.
  • one or more compounds of Formula I in the manufacture of a medicament for the treatment of obesity, hyperphagia, obsessive/compulsive disorder, depression, anxiety, substance abuse, sleep disorder, hot flashes, and/or hypogonadism.
  • Particularly preferred embodiments of this aspect of the invention include the use of one or more compounds of Formula I in the manufacture of medicaments for the treatment of obesity, obsessive/compulsive disorder, depression, and/or anxiety.
  • the present invention provides a pharmaceutical formulation adapted for the treatment of obesity, or for the treatment of obsessive/compulsive disorder, or for the treatment of depression, or for the treatment of anxiety, each of which comprise a compound of Formula I in association with a pharmaceutically acceptable carrier, diluent or excipient.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group.
  • n-alkyl refers to an unbranched alkyl group.
  • (C 1 -C 2 )alkyl refers to methyl and ethyl.
  • (C 1 -C 3 ) n -alkyl refers to methyl, ethyl, and propyl.
  • (C 1 -C 3 )alkyl refers to methyl, ethyl, propyl, and isopropyl.
  • (C 1 -C 5 )alkyl refers to all branched and unbranched alkyl groups having from one to five carbon atoms.
  • (C 1 -C 6 )alkyl refers to all branched and unbranched alkyl groups having from one to six carbon atoms.
  • (C 3 -C 6 )alkyl refers to all branched and unbranched alkyl groups having from three to six carbon atoms.
  • (C 2 -C 6 )alkyl refers to all branched and unbranched alkyl groups having from two to six carbon atoms.
  • (C x -C y )alkyl may also be used in conjunction with other substituents to indicate a branched or unbranched saturated hydrocarbon linker for the substituent, where x and y indicate the range of carbon atoms permitted in the linker moiety.
  • -(C 0 -C 1 )alkyl refers to a single bond or a methylene linker moiety
  • -(C 0 -C 2 )alkyl refers to a single bond, methylene, methyl-methylene, or ethylene linker moiety
  • -(C 0 -C 3 )alkyl further includes trimethylene, alpha- or beta-methyl ethylene, or ethyl methylene
  • -(C 0 -C 5 )alkyl refers to a bond or a saturated, branched or unbranched hydrocarbon linker having from 1 to 5 carbon atoms.
  • -(C 1 -C 2 )alkyl, -(C 1 -C 3 )alkyl, -(C 1 -C 5 alkyl, and -(C 1 -C 6 )alkyl refer to branched or unbranched alkylene linkers having from 1 to 2, 3, 5, or 6 carbon atoms, respectively.
  • alkenyl refers to a branched or unbranched hydrocarbon group having one or more carbon-carbon double bonds.
  • (C 3 -C 7 )cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkylakyl refers to a cycloalkyl moiety linked through a branched or unbranched alkylene linker, as for example, but without limitation, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH(CH 2 CH 3 )-, and the like.
  • (C 3 -C 7 )cycloalkyl(C 0 -C 1, 2 or 3 )alkyl refers to a cycloalkyl moiety linked through a single bond (i.e. C 0 -alkyl) or an alkylene linker having 1, 2, or 3 carbon atoms, respectively.
  • Each alkyl, cycloalkyl, and cycloalkylalkyl group may be optionally substituted as provided for herein.
  • alkoxy refers to an alkyl group, phenyl group, sulfonyl group, or carbonyl group, respectively, that is bonded through an oxygen atom.
  • alkylthio trifluoromethylthio
  • cycloalkylthio cyclohexylthio
  • alkylcarbonyl refers to an alkyl, alkoxy, phenyl, or phenyloxy group bonded through a carbonyl moiety.
  • alkylsulfonyl ( t- butylsulfonyl), "(C 3 -C 7 )cycloalkylsulfonyl", "phenylsulfonyl”, “Ph 1 -(C 0 -C 3 )alkylsulfonyl”, and "Ar 2 -(C 0 -C 3 )alkylsulfonyl”, refer to an alkyl ( t- butyl), (C 3 -C 7 )cycloalkyl, phenyl, Ph 1 -(C 0 -C 3 )alkyl, or Ar 2 -(C 0 -C 3 )alkyl group bonded through a sulfonyl moiety (-SO 2 -).
  • N-linked means that the referenced moiety is linked through its nitrogen atom
  • N-linked Het 1 means the Het 1 moiety is linked through a nitrogen atom in the ring of the Het 1 moiety.
  • halo refers to fluoro, chloro, bromo, or iodo.
  • Preferred halo groups are fluoro, chloro, and bromo. More preferred halo groups are fluoro and chloro.
  • heterocycle is taken to mean a saturated or unsaturated 4 to 7 membered ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, said ring optionally being benzofused.
  • exemplary saturated heterocycles include azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like.
  • Exemplary unsaturated heterocycles include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, and the like.
  • Exemplary benzofused heterocyclic rings include, but are not limited to, indolyl, dihydroindolyl, indazolyl, benzisoxazolyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzoxazolyl, benzo[1,3]dioxolyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzopyranyl, dihydrobenzopyranyl, cinnolinyl, quinazolinyl and the like, all of which may be optionally substituted as provided for herein, which also includes optionally substituted on the benzene ring when the heterocycle is benzofused.
  • preferred saturated heterocycles include pyrrolidinyl, piperidinyl, homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, homomorpholinyl, and homothiomotpholinyl, all of which may be optionally substituted as provided for herein.
  • preferred unsaturated heterocycles include [pyrrolyl,?] pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, and pyridyl, all of which may be optionally substituted as provided for herein.
  • gem- refers to two identical substituents bonded to a common carbon atom, as for example, but without limitation, gem-methyl, meaning two methyl groups bound to a common carbon atom, as for instance in a 3,3-dimethyltetrahydrobenzofuranyl group.
  • gem-ethano means an ethylene substituent wherein both carbons are bound to the same carbon atom of the substituted group to form a cyclopropyl moiety, as for example, but without limitation, the ethano substituent on the 2-phenyl-(1,1-ethano)ethylamino group below:
  • amino protecting group refers to a substituent commonly employed to block or protect the amino functionality while reacting other functional groups on the compound.
  • amino protecting groups include the formyl group, the trityl group, the acetyl group, the trichloroacetyl group, the trifluoroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, carbamoyl-type blocking groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"), t- butoxycarbonyl ( t- BOC), and like amino protecting groups.
  • FMOC 9-fluorenylmethoxycarbonyl
  • t- BOC t- butoxycarbonyl
  • the species of amino protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of subsequent reactions on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • the selection and use (addition and subsequent removal) of amino protecting groups is well known within the ordinary skill of the art. Further examples of groups referred to by the above terms are described by T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley and Sons, New York, NY, 1999, chapter 7 , hereafter referred to as " Greene ".
  • pharmaceutical or “pharmaceutically acceptable” when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the recipient.
  • pharmaceutical composition it is further meant that the carrier, solvent, excipients and/or salt must be compatible with the active ingredient of the composition (e.g. a compound of Formula I). It is understood by those of ordinary skill in this art that the terms “pharmaceutical formulation” and “pharmaceutical composition” are generally interchangeable, and they are so used for the purposes of this application.
  • an effective amount means an amount of a compound of Formula I which is capable of activating 5-HT 2C receptors and/or eliciting a given pharmacological effect.
  • suitable solvent refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
  • compounds of the present invention may exist as stereoisomers. As such, all enantiomers, diastereomers, and mixtures thereof, are included within the scope of the present invention. Where specific stereochemistries are identified in this application, the Cahn-Prelog-Ingold designations of (R)- and (S)- and the cis and trans designation of relative stereochemistry are used to refer to specific isomers and relative stereochemistry. Known optical rotations are designated by (+) and (-) for dextrorotatary and levorotatary, respectively. Where a chiral compound is resolved into its isomers, but absolute configurations or optical rotations are not determined, the isomers are arbitrarily designated as isomer 1, isomer 2, etc. While all enantiomers, diastereomers, and mixtures thereof, are contemplated within the present invention, preferred embodiments are single enantiomers and single diastereomers.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric acid, and the like.
  • Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
  • Such pharmaceutically acceptable salts thus include chloride, bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, propiolate, propionate, phenylpropionate, sal
  • pyrid-2-yls are preferred over pyrid-3-yls (ring numbering being with respect to the pyridyl nitrogen to the attachment position of the pyridyl moiety to the core structure irrespective of further substituents on the pyridyl that might change the ring numbering of the final compound according to IUPAC nomenclature rules).
  • R 10 or R 11 is phenyl
  • substitution at the para-position of the phenyl moiety is particularly preferred.
  • substitution at 4- position relative to the attachment point of the heterocycle to the core structure is also particularly preferred.
  • R 10 , R 11 , or R 13 is a 5 member heterocycle
  • substitution at the 3- and 4-positions is particularly preferred over substitution at the 2 or 5-position, relative to the attachment point of the heterocycle to the core structure.
  • R 6 is -(C 1 -C 3 )alkyl-S-(C 0 -C 3 )alkyl-R 10 are preferred over compounds wherein R 6 is -(C 1 -C 3 )alkyl-NR 11 R 12 , which are generally preferred over compounds wherein R 6 is -(C 1 -C 3 )alkyl-O-R 13 .
  • preferred compounds are those having a methylene ((C 1 )alkyl) linker between the tetrahydrobenzazepine core structure and the heteroatom (i.e. compounds wherein R 6 is -CH 2 -S-(C 0 -C 3 )alkyl-R 10 ).
  • Additional preferred compounds within the thioether sub-family of compounds are those having a direct bond ((Co)alkyl) between the sulfur atom and the R 10 moiety (i.e. compounds wherein R 6 is -(C 1 -C 3 )alkyl-S-R 10 ).
  • particularly preferred compounds within the thioether sub-family of compounds are those having both a methylene linker between the tetrahydrobenzazepine core structure and the sulfur atom and a direct bond to R 10 (i.e. compounds wherein R 6 is -CH 2 -S-R 10 ).
  • R 7 to be halo, more particularly chloro, and/or for R 1-5.8.9 to each be hydrogen to provide yet more preferred embodiments of the present invention.
  • One favored group of compounds of the present invention is that represented by formula (1a), and pharmaceutically acceptable salts thereof: wherein R 10 is as defined in formula (I).
  • Another favored group of compounds of the present invention is that represented by formula (Ib), and pharmaceutically acceptable salts thereof: wherein R 11 is as defined in relation to formula (I).
  • Yet another favored group of compounds of the present invention is that represented by formula (Ic), and pharmaceutically acceptable salts thereof: wherein R 13 is as defined in formula (I).
  • Specific preferred compounds of the present invention are those described in the Examples herein, including the free bases and the pharmaceutically acceptable salts thereof.
  • the compounds of the invention can be prepared according to the following synthetic schemes by methods well known and appreciated in the art. Suitable reaction ' conditions for the steps of these schemes are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will be appreciated by those skilled in the art that synthetic intermediates may by isolated and/or purified by various well known techniques as needed or desired, and that frequently, it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical.
  • a 6-alkyl-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine derivative (aa) that is substituted with a leaving group X for example a 6-chloroalkyl derivative of the 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines (aa) with an appropriately substituted thiol (ba), and a base in a suitable solvent, typically sodium hydride in DMF, and stir at room temperature or heat to afford the desired compound (bb) after applying standard extractive and chromatographic techniques.
  • a suitable solvent typically sodium hydride in DMF
  • a thiolate salt for example potassium thiolate
  • aa electrophile
  • Thiols are either commercially available or may be prepared by methods well known to the skilled artisan. Deprotection of the ring nitrogen gives the desired compound (Ia).
  • Another possible synthetic route to the N -protected thioether derivatives (bb) via intermediates (bc) and (bd) is also illustrated in Scheme I.
  • a 6-alkyl-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine derivative (aa) that is substituted with a leaving group X for example a 6-chloroalkyl derivative of the 2,3,4,5-tetrahydro-1 H- benzo[ d ]azepines (aa)
  • a leaving group X for example a 6-chloroalkyl derivative of the 2,3,4,5-tetrahydro-1 H- benzo[ d ]azepines (aa)
  • thiourea in a suitable solvent and usually under heat to give after workup intermediate (bc).
  • Treatment of intermediates (bc) in a suitable solvent with aqueous sodium hydroxide and heat may afford after applying extractive and chromatographic techniques thiol intermediates (bd).
  • the thioether derivatives (bb) may be prepared from the thiols (bd) by palladium-catalyzed reactions with an appropriately substituted aryl or heteroaryl bromide.
  • the aryl or heteroaryl bromides are either commercially available or can be synthesized by methods well known to the skilled artisan.
  • compounds (cb) may be obtained by reaction of 6-alkyl alcohols (ab) with an appropriately substituted alkyl halide (cc) or alkyl sulfonate (cc) in the presence of a suitable base and in a suitable solvent. Deprotection of the ring nitrogen gives the desired compounds (Ib) where R 3 is H.
  • Final compounds (Ib), where R 1 is methyl or ethyl, can be obtained by alkylation of the secondary amine after removal of Pg 1 .
  • the appropriate 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines (aa) containing a suitable leaving group may be prepared from the appropriate alcohols (ab) via transformations well known in the art.
  • the alcohols (ab) may be obtained from the appropriate 6-triflates of 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines (d) following reaction processes well known to the skilled artisan, some of which are described in Schemes III to V.
  • the appropriate 6-chloromethyl derivatives of 2,3,4,5-tetrahydro-1 H- benzo[ d ]azepines may be prepared as described in Scheme III.
  • a solvent typically DMSO
  • Reduction of the carboxylic ester with a reducing agent, such as lithium aluminum hydride, and subsequent protection of the nitrogen with a suitable protecting group for a secondary amine such as, but not limited to, tert-butoxycarbonyl, provides compounds (ad).
  • the alcohol (ad) may be converted into the chloride (ac), for example, by treatment with methanesulfonyl chloride in a solvent, typically dichloromethane, using triethylamine as base.
  • the appropriate 6-(1-hydroxy)-ethyl derivative of the 2,3,4,5-tetrahydro-1 H- benzo[ d ]azepines may be prepared from the appropriate 6-triflate of 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines (d) as described in Scheme IV.
  • Compounds (ha) may be prepared by Heck coupling of the appropriate 6-triflate of 2.3,4,5-tetrahydro-1 H- benzo[ d ]azepines (d) with butyl vinyl ether, using a suitable palladium catalyst/ligand mixture in a solvent, typically DMF, and triethylamine as base. Acid hydrolysis and standard extractive and chromatographic techniques afford the desired compounds (ha).
  • a suitable protecting group for a secondary amine such as, but not limited to, tert -butoxycarbonyl
  • a suitable protecting group for a secondary amine such as, but not limited to, tert -butoxycarbonyl
  • ketones (hb) may be converted in tertiary alcohols (i) by addition of a carbon nucleophile.
  • Alcohols with a 2-carbon linker (jb) or a 3-carbon linker (kb) may be prepared from the appropriate 6-triflate of 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines (d) as described in Scheme V.
  • Compounds (ja) may be prepared by Heck coupling of the appropriate 6-triflate of 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines (d) with, for example, 1-methoxy-trimethylsilyloxy-ethylene using a suitable palladium catalyst/ligand mixture in a solvent, typically DMF, and in the presence of lithium acetate. Standard work-up and isolation techniques afford the desired compounds (ja).
  • Compounds (ka) may be prepared by Heck coupling of the appropriate 6-triflate of 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines (d) with, for example, t-butyl acrylate using a suitable palladium catalyst/ligand mixture, for example PD(II) acetate/tri-o-tolylphosphine, in a solvent, typically DMF, and triethylamine as base. Standard work-up and isolation techniques afford the desired compounds (ka).
  • esters (kb) Reduction of the double bond, for example with hydrogen and Pd/C in a solvent such as methanol, affords esters (kb).
  • the esters may be reduced to the alcohols (kc) under conditions well known in the literature.
  • the intermediate esters (ja), (ka), and (kb) might be further alkylated under methods well known in the art to provide eventually alcohols with branched alkyl chains.
  • the appropriate 6-aminoalkyl derivatives of 2,3,4,5-tetrahydro-1 H- benzo[ d ]azepines (m) can be converted to the compounds (n), where R 11 is directly attached to the nitrogen (-L-HN-R 11 ), under Buchwald coupling conditions, by treatment with an appropriate aryl bromide, chloride, iodide, or triflate in the presence of an effective palladium catalyst/ligand system, and a base in a suitable solvent, typically toluene or 1,4-dioxane under an inert atmosphere and heat.
  • the aryl halides or triflate are either commercially available or may be prepared by methods well known to the skilled artisan.
  • the appropriate 6-aminoalkyl derivative of 2,3,4,5-tetrahydro- 1H- benzo[ d ]azepines may be prepared from the appropriate 6-triflate of 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines (d) as described in Schemes VII and VIII. Mix the appropriate 6-triflate of 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines (d) with zinc cyanide and a suitable palladium catalyst/ligand mixture in a solvent, typically DMF, to obtain the desired 6-cyano-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines (p) after standard extractive and chromatographic techniques.
  • 6-aminoalkyl derivatives (m) may be prepared as described in Scheme VIII. Reaction of the 6-alkyl halides or sulfonates (aa) with a nitrogen nucleophile, such as sodium azide, in a suitable solvent, such as DMF, can afford azides (s), which may be reduced to the amino derivatives (m) by methods well known to the skilled artisan. Alternately, reaction of the 6-alkyl halides or sulfonates (aa) with cyanide can lead to compounds (t), which may be reduced to the amino derivatives (u) by methods well known to the skilled artisan.
  • a nitrogen nucleophile such as sodium azide
  • a suitable solvent such as DMF
  • reaction of the 6-alkyl halides or sulfonates (aa) with cyanide can lead to compounds (t), which may be reduced to the amino derivatives (u) by methods well known to the skilled artisan.
  • the appropriate 6-triflate of 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines may be prepared as described in Scheme IX.
  • Compound (d) may be prepared from 1-naphthol.
  • 1-Naphthol can be converted to 5-hydroxy-1,4-dihydronaphthalene (va) by Birch reduction using ammonia and lithium metal at low temperature. Methylation of the 6-hydroxy group affords the compound (vb).
  • Ozonolysis of compound (vb) and subsequent reduction with sodium borohydride provide the diol (vc).
  • the appropriate 6-triflate of 2,3,4,5-tetrahydro-1 H -benzo[ d ]azepines may be prepared as described in Scheme II.
  • Compound (a) may be prepared from 1-naphthol.
  • 1-Naphthol can be converted to 5-hydroxy-1,4-dihydronaphthalene (c) by Birch reduction using ammonia and lithium metal at low temperature. Methylation of the 6-hydroxy group affords the compound (d).
  • Ozonolysis of (d) and subsequent reduction with sodium borohydride provide the diol (e).
  • 5-Methoxy-1,4-dihydronaphthalene Add powdered potassium carbonate (193.1 g, 1.397 mol) to a solution of 5-hydroxy-1,4-dihydronaphthalene [68.08 g, 90% potency based on 1 H-NMR, 0.4657 mol, from Societa Italiana Medicinala Scandicci, s.r.l., Reggello (Firenze), Italy] in ethanol (700 mL). Cool the solution to 0°C with ice/water and add dimethyl sulfate (88.1 g, 66.1 mL, 0.699 mol) dropwise, maintaining the temperature between 5°C and 10°C.
  • 2,3-Bis-(2-hydroxyethyl)-1-methoxybenzene Charge a four-neck 5 L flask equipped with an over-head mechanical stirrer, reflux condenser, thermocouple, and gas dispersion apparatus with 5-methoxy-1,4-dihydronaphthalene (264.54 g, 89.5% potency based on 1 H-NMR, 1.478 mol) in DCM (1.3 L) and 2B-3 ethanol (1 L). Add sudan III (10 mg) to give a faint red color.
  • 2,3-Bis-(2-methanesulfonyloxyethyl)-1-methoxybenzene To a slurry of 2,3-bis-(2-hydroxyethyl)-1-methoxybenzene (50.6 g, 0.258 mol, 1 equiv.) and triethylamine (78.3 g, 0.774 mol, 3 equiv.) in DCM (500 mL) at 0°C, add dropwise a solution of methanesulfonyl chloride (65.0 g, 0.567 mol, 2.2 equiv.) in DCM (100 mL) over 45 min.
  • methanesulfonyl chloride 65.0 g, 0.567 mol, 2.2 equiv.
  • 6-Methoxy-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine Dissolve 2,3-bis-(2-methanesulfonyloxyethyl)-1-methoxybenzene (474.4 g, 1.346 mol) in acetonitrile (7 L) and split the mixture into two equal lots. In two separate runs, add concentrated aqueous NH 4 OH (3.5 L) and charge the solution to a pressure vessel (PARR apparatus). Heat the solution in a closed reactor to 100°C over 20 min (internal pressure reaches about 100 psi), and maintain at 100°C until the reaction is complete (about 1 h, HPLC monitored). Cool the reaction mixture to ambient temperature.
  • PARR apparatus pressure vessel
  • 6-Methoxy-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine Hydrochloride Dissolve crude 6-methoxy-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine (35.1 g, 0.198 mol) in 2B-3 ethanol (250 mL), heat the solution to reflux and add 2M HCl in ethanol (108.9 mL, 0.218 mol, 1.1 equiv.). Slowly add heptane (700 mL) over 10 min, then remove the heating mantle and cool the solution to ambient temperature, and finally continue the cooling with an ice/water mixture.
  • 6-Methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine To a slurry of 6-methoxy-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine hydrochloride (35.3 g, 0.165 mol, 1 equiv.) and triethylamine (69.1 mL, 0.496 mol, 3 equiv.) in DCM (300 mL) cooled at 0°C with ice/water, add dropwise a solution of trifluoroacetic anhydride (25.7 mL, 0.182 mol, 1.1 equiv.) in DCM (40 mL) over 30 min, but at a rate that maintains the temperature below 10°C.
  • 6-Hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine To a 1M solution of BBr 3 (1.1 L, 1.6 equiv.), cooled at 0°C with an ice-water bath, add 6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine (187 g, 0.684 mol) in DCM (200 mL) over 1 h., while maintaining the temperature between 0°C and 10°C.
  • 6-Acetyl-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine Combine 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1 H- benzo[ d ]azepine (0.6 g, 1.41 mmol), butyl vinyl ether (0.9 mL, 7.06 mmol), palladium(II) acetate (32 mg, 0.14 mmol), DPPP (58 mg, 0.14 mmol), triethylamine (90.4 mL, 2.82 mmol), anhydrous DMF (10 mL) and stir at 90°C for 2 h.
  • 6-Acetyl-3- tert -butoxcarbonyl-7-chloro-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine Dissolve 6-acetyl-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1 H- benzo[ d ]azepine (1.3 g, 4.24 mmol) in methanol (42 mL). Add K 2 CO 3 (1.2 g, 8.49 mmol) and stir at 80°C for 2 h.
  • 6-Hydroxy-nicotinoyl chloride Mix 6-hydroxy-nicotinic acid (14 g, 101 mmol) and pyridine (0.41 mL, 0.49 mmol) in acetonitrile (60 mL). Heat the mixture at 80°C for 30 min. Add thionyl chloride (7.6 mL, 104 mmol) and continue heating at 80°C for an additional 1.5 h. Cool to room temperature (reaction solidifies). Filter off the solid using a minimal amount of cold acetonitrile. Dry the solid in vacuo to obtain the desired intermediate as a tan solid (11.2 g, 70%).
  • 6-Hydroxy- N- methoxy- N- methyl-nicotinamide Add 6-hydroxy-nicotinoyl chloride (11.2 g, 71 mmol) and N,O -dimethylhydroxylamine hydrochloride (7.76 g, 79.5 mmol) to ethanol-free chloroform (100 mL, wash chloroform with water, dry over MgSO 4 , then filter through neutral alumina to obtain ethanol-free chloroform). Cool the mixture to 0°C under a nitrogen atmosphere. Add pyridine (12.6 mL, 155.8 mmol), warm reaction up to room temperature and stir for 16 h under a nitrogen atmosphere.
  • 2-Hydroxy-5-(3-methyl-butyryl)-pyridine Dissolve 6-hydroxy- N- methoxy- N- methyl-nicotinamide (1.89 g, 10.4 mmol) in anhydrous THF (40 mL), then cool the solution to 0°C. Add isobutyl magnesium chloride (16 mL, 32 mmol, 2M solution in diethyl ether) under nitrogen, allow the mixture to warm gradually to room temperature and then stir for 16 h. Quench the reaction with 1M aqueous HCl and concentrate the mixture in vacuo. Extract the aqueous mixture with EtOAc (4 ⁇ 50 mL).
  • 2-Mercapto-5-(3-methyl-butyryl)-pyridine Combine 2-hydroxy-5-(3-methyl-butyryl)-pyridine (742 mg, 4.1 mmol) and phosphorus pentasulfide (1.88 g, 4.2 mmol) in pyridine (5 mL). Heat the mixture at 120°C for 5 h under a nitrogen atmosphere. Cool the mixture to room temperature and partition between water and EtOAc. Collect the aqueous layer, wash with additional EtOAc and DCM. Acidify the aqueous layer with 1M aqueous HCl and extract with DCM (4 ⁇ 30 mL). Dry the combined organic extracts over MgSO 4 , filter and concentrate in vacuo to obtain the title compound (120 mg, 15%). MS (ES+) mlz: 196.2 (M+H) + .
  • the compound of Preparation 13 may be prepared essentially as described in Preparation 12 using 1-bromo-2-butanone. Overall yield and MS (ES+) data are shown in the Table below. Prep. Structure Compound Yield (%) MS (ES+) m / z 13 4-Ethyl-1 H -imidazole-2-thiol 63 129 (M+H) +
  • 2-Amino-cyclohexanone Hydrochloride Add 2-nitrocyclohexanone (7.0 g, 48.9 mmol), 5% platinum sulfided on carbon (500 mg), ethanol (120 mL) and concentrated hydrochloric acid (6 mL) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 50 psi with hydrogen and stir the mixture for 3 h. Filter the mixture through Celite® and wash with ethanol followed by DCM under a nitrogen atmosphere. Concentrate the filtrate in vacuo. Slurry the residue in acetone (50 mL) and filter. Collect the solid to obtain the desired intermediate (2.2 g, 40%).
  • the compound of Preparation 16 may be prepared essentially as described in Preparation 15 using isovaleryl chloride. Yield is shown in the Table below. Prep. Structure Compound Yield (%) 16 5- iso -Butyl-1 H -1,3,4-triazole-2-thione 60
  • 2-Methyl-1 H -imidazole-4-sulfonyl chloride Carefully add chlorosulfonic acid (30 mL) to neat 2-methylimidazole (5 g, 60.9 mmol). Heat the mixture at 150°C for 3 h and cool to room temperature. Add thionyl chloride (10 mL), heat at 100°C for 3 h and cool to room temperature. Carefully pour the mixture into ice. Slowly add solid sodium carbonate to neutralize the solution. Filter the precipitate formed and wash with water. Dry the solid under high vacuum overnight at 45°C to give the desired intermediate (4.38 g, 40%). MS (ES+) mlz : 181 (M+H) + .
  • N -[4-(6-Bromo-pyridin-3-yl)-thiazol-2-yl]-cyclopropylmethylamine Slurry crude 2-bromo-1-(6-bromo-pyridin-3-yl)-ethanone (11.5 g, ca. 48%), N -cyclopropylmethyl thiourea (2.2 g, 16.9 mmol) and sodium bicarbonate (1.7 g, 20 mmol) in ethanol (100 mL) at room temperature. Stir the mixture at reflux for 1 h under a nitrogen atmosphere. Turn off heat and stir the mixture for an additional 16 h at room temperature.
  • Example 2 may be prepared essentially as described in Example 1 by using 6-aminomethyl-3- tert -butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine and bromobenzene.
  • the overall yield and MS (ES+) data are shown in the Table below. Ex. Structure Compound Yield (%) MS (ES+) m / z 2. 7-Chloro-6-phenylaminomethyl-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine Succinate 23 287.2 (M+H) +
  • Examples 5-9 may be prepared essentially as described in Example 4 by using 3- tert -butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine and the appropriate thiol.
  • Example 8 may be prepared essentially as described in Example 4 by using 3- tert -butoxycarbonyl-7-chloro-3- tert -butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine and 2 H -pyridazine-3-thione.
  • Example 9 may be prepared essentially as described in Example 4 by using 3- tert -butoxycarbonyl-7-chloro-3- tert -butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine and 4-fluorophenol. Overall yields and MS (ES+) data are shown in the Table below.
  • Examples 12-14 may be prepared essentially as described in Example 11 by using 3- tert -butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine and the appropriate thiol. Overall yields, MS (ES+) data and optical rotation (where applicable) are shown in the Table below.
  • Examples 17-21 may be prepared essentially as described in Example 16 by using 3- tert -butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepine and the appropriate thiol.
  • Example 21 was prepared as Succinate by following the procedure described in General Procedure 2-1. Overall yields and MS (ES+) data are shown in the Table below.
  • Examples 23-24 may be prepared essentially as described in Example 22 by using 3- tert -butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1 H- benzo[ d ]azepine and the appropriately substituted thiol. Overall yields and MS (ES+) data are shown in the Table below.
  • Examples 27-31 may be prepared essentially as described in Example 26 by using 3- tert -butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1 H- benzo[ d ]azepine and the appropriate thiol. Overall yields and MS (ES+) data are shown in the Table below.
  • Second eluting isomer had 96.6% ee [Analytical chiral conditions: Chiralcel OD-H column 0.46x15 cm, eluting with heptane/ n -propanol (9:1)].
  • Examples 35-37 may be prepared essentially as described in Example 34 using 3- tert -butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1 H- benzo[ d ]azepine and the appropriately substituted 1 H- 1,3,4-triazole-2-thione. Overall yields and MS (ES+) data are shown in the Table below.
  • Second fraction eluted at 80% acetonitrile in 0.3% TFA/H 2 0, and contained 3- tert -butoxycarbonyl-7-chloro-6-(2-methyl-2 H- [1,2,3]triazol-4-ylthiomethyl)-2,3,4,5-tetrahydro-1 H- benzo[ d ]azepine (58.8 mg, 23%).
  • the compounds of the present invention are relatively selective for the 5-HT 2C receptor.
  • the compounds of the present invention are particularly relatively selective for the 5-HT 2C receptor in comparison to other 5-HT receptor subtypes and specifically the 5-HT 2A and 5-HT 2B receptors. This selectivity is demonstrated in the following agonist activity assays and receptor binding assays.
  • the 5-HT 2 receptors are functionally coupled to specific G-proteins: Agonist activation of 5-HT 2 G-protein-coupled receptors results in the release of GDP from the ⁇ -subunit (G alpha q or G alpha i) of the G-protein and the subsequent binding of GTP.
  • the binding of the stable analog GTP ⁇ [ 35 S] is an indicator of receptor activation (i.e. agonist activity).
  • the G alpha q-GTP ⁇ [ 35 S] binding assay is used to determine the in vitro potency (EC 50 ) and maximal efficacy (E max , normalized to the 5-HT response) of a test compound at the 5-HT2 A , 5-HT 2B , and 5-HT 2C receptors.
  • the area under the dose response curve (AUC) is also determined for each receptor subtype and used to measure the test compound's selectivity for the 5-HT 2C receptor over the 5-HT 2A and 5-HT 2B receptors, expressed as Selectivity Ratios (AUC 2C/2A and AUC 2C/2B, respectively).
  • the Selectivity Ratios allow the assessment of selectivity based on both potency and efficacy.
  • Membrane Preparation Grow AV 12 cells stably transfected with the human 5-HT 2A , 5-HT 2B or 5-HT 2C receptors in suspension, harvest by centrifugation, wash the cell pellet with phosphate buffered saline, pH 7.4, pellet the cells again, remove the supernatant, freeze the cell pellet on dry ice and store at -70°C. Thaw stock cell pellet and resuspend in 50mM Tris, pH 7.4, aliquot into 1-2 mL volumes and refreeze at -70°C for subsequent assays. (As is appreciated in the art, optimal cell quantities used per aliquot will vary with the individual transfected cell line used. In one embodiment, 5-HT 2A and 5-HT 2C transfected cells are typically used at about 6 x 10 8 cells per aliquot, while 5-HT 2B cells are typically used at about 7.5 x 10 8 cells per aliquot).
  • assay buffer 50 mM Tris-HCl (pH 7.4), 10 mM MgCl 2 , 100 mM NaCl, and 0.2 mM EDTA
  • assay buffer 50 mM Tris-HCl (pH 7.4), 10 mM MgCl 2 , 100 mM NaCl, and 0.2 mM EDTA
  • resuspend in assay buffer and incubate for 10 min. at 37°C to hydrolyze any residual endogenous 5-HT.
  • G alpha q-GTP ⁇ [ 35 S] Binding Assays The immunoadsorption scintillation proximity assay (ISPA) of [ 31 S]-GTP ⁇ S binding to G alpha q is modified from published conditions ( DeLapp et al, JPET 289 (1999) 946-955 ). Dissolve test compounds in DMSO and dilute in assay buffer to provide a range of concentrations to generate a concentration response curve. In wells of a 96 well microtiter plate, mix diluted test compound, GDP (0.1 ⁇ M final concentration), and [ 35 S]-GTP ⁇ S (between 0.5 and 1.0 nM final concentration).
  • ISPA immunoadsorption scintillation proximity assay
  • the AUC for the test compound for each receptor subtype as described above.
  • the normalized AUC for a test compound at a given receptor is therefore expressed as a percentage of the AUC determined for 5-HT at that receptor.
  • the AUC 2C/2A and AUC 2C/2B for 5-HT are each 1.0.
  • the ratios for mCPP meta -chlorophenylpiperazine are tested and are found to be 2.1 and 2.1 respectively.
  • Representative compounds of the present invention are tested in the G alpha q-GTP ⁇ [ 35 S] assays for the 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors essentially as described above and are found to be a highly potent and selective agonists of the 5-HT 2C receptor, with EC 50 's typically less than or equal to 250 nM, and AUC 2C/2A and AUC 2C/2B ratios typically greater than 1.5.
  • Preferred compounds are those with EC50's less than or equal to 100 nM, and AUC 2C/2A and AUC 2C/2B ratios greater than or equal to 2.0. More preferred are those with EC50's less than or equal to 50 nM, and AUC 2C/2A and AUC 2C/2B ratios greater than or equal to 3.0.
  • the ligand binding affinity of the compounds of the present invention to the 5-HT 2C receptor subtype is measured essentially as described by Wainscott ( Wainscott, et al., Journal of Pharmacology and Experimental Therapeutics, 276:720-727 (1996 )). Data is analyzed by nonlinear regression analysis on the concentration response curves using the four parameter logistic equation described by DeLean ( DeLean, et al., Molecular Pharmacology, 21, 5-16 (1982 )). IC 50 values are converted to K i values using the Cheng-Prusoff equation ( Cheng, et al., Biochem. Pharmacol., 22, 3099-3108 (1973 )).
  • Representative compounds of the present invention are tested essentially as described above and are found to have excellent affinity for the 5-HT 2C receptor, with K i 's typically less than or equal to about 250 nM.
  • Preferred compounds are those with K i 's of less than or equal to about 100 nM. More preferred are those with K i 's less than or equal to 50 nM.
  • Affinities for other receptor subtypes can readily be determined by slight modification of the above described radioligand receptor binding assay using cells transfected with the desired receptor in place of cells transfected with the 5-HT 2C receptor subtype and using an appropriate radioligand.
  • the binding affinities for representative compounds of the present invention for a variety of receptors are determined in such assays and the compounds are found to have surprisingly higher affinity for the 5-HT 2C receptor.
  • Affinity for the 5-HT 2C receptor is found to be significantly higher than for other 5-HT receptor subtypes, and notably higher than the 5-HT 2A and 5-HT 2B receptor subtypes.
  • Preferred compounds are those with IC 50 's equal to or greater than 300 nM for the alpha 1 and alpha2 adrenergic receptors and equal to or greater than 500 nM for D 1 and D 2 dopaminergic receptors. More preferred compounds are those with IC 50 's equal to or greater than 1000 nM for the alpha 1 and alpha 2 adrenergic receptors and the D 1 and D 2 dopaminergic receptors. Still more preferred are those compounds with IC 50 's equal to or greater than 3000 nM for the alpha 1 and alpha 2 adrenergic receptors and the D 1 and D 2 dopaminergic receptors.
  • exemplified compounds are assayed and found to have either an EC 50 or a K i value of equal to or less than 50 nM, and to have AUC 2C/2A and AUC 2C/2B ratios of greater than or equal to 2.0.
  • Exemplified compounds are assayed and found to typically have alpha 1 and alpha 2 adrenergic receptor IC 50 's equal to or greater than 300 nM, and D 1 and D 2 dopaminergic receptor IC 50 's equal to or greater than 500 nM.
  • the ability of the compounds of the present invention to treat obesity is demonstrated by testing in acute and chronic rat feeding assays.
  • mice Obtain male Long-Evans rats (Harlan Sprague-Dawley, Indianapolis, IN) that are approximately one hundred-days old and have been maintained on a calorie rich diet since weaning (TD 95217, 40% calories from fat; Teklad, Madison, WI). House the rats individually with a 12 h:12 h light:dark cycle (lights on from about 22:00 h to about 10:00 h) and maintain rats on the same diet (TD 95217) with free access to water, for about 1-2 weeks to acclimate the rats to the environment. Dose rats orally with vehicle (10% acacia with 0.15% saccharin in water) once daily for at least 1 day (typically 1-2 days) to acclimate the rats to the procedures. Randomize the rats into groups so each group has similar mean body weights.
  • Calorimetric Acute Feeding Assay At approximately 8:00 h on the day of assay, weigh each rat and transfer to individual chambers of an open circuit calorimetry system (Oxymax, Columbus Instruments International Corporation; Columbus, OH), with free access to food (pre-weighed) and water, and begin measuring VO 2 and VCO 2 . At approximately 10:00 h, dose rats orally with vehicle or test compound, return them to their calorimetry chambers, and continue measuring VO 2 and VCO 2 at regular time intervals (approximately hourly). At approximately 8:00 h the following day, measure rat body weight and the remaining food, assuming the difference in weight of food is equal to the mass of food consumed.
  • Acute Feeding Assay with a selective 5-HT 2C receptor antagonist The above calorimetric acute feeding assay is conducted with the following modifications. Open circuit calorimetry systems are not used and only the 24 h periodic food intake and body weight are measured. Three groups of rats are used with the first group receiving a subcutaneous dose of saline (0.5 mL) about 15 minutes prior to the oral dose of vehicle, the second group receiving a subcutaneous dose of saline (0.5 mL) about 15 minutes prior to the oral dose of test compound in vehicle, and the third group receiving a subcutaneous injection of a selective 5-HT 2C receptor antagonist, 6-chloro-5-methyl-N- ⁇ 2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbonyl ⁇ -2,3-dihydroindole (3 mg/Kg, in 35% cyclodextrin, 0.5 mL), about 15 min.
  • Chronic Feeding Assay At between approximately 8:00 h and 10:00 h on day one of the assay, weigh and orally dose each rat with vehicle or test compound and return the animal to its home cage, with free access to food (pre-weighed) and water. For each of days 2-15, at between approximately 8:00 h and 10:00 h, measure rat body weight and the weight of food consumed in the last 24 h period, and administer daily oral dose of test compound or vehicle. On days -2 and 15 measure total fat mass and lean mass by nuclear magnetic resonance (NMR) using an EchoMRITM system (Echo Medical Systems, Houston Texas). (See Frank C. Tinsley, Gersh Z. Taicher, and Mark L. Heiman, "Evaluation of a New Quantitative Magnetic Resonance (QMR) Method for Mouse Whole Body Composition Analysis", Obesity Research, submitted May 1, 2003 .)
  • NMR nuclear magnetic resonance
  • Representative compounds of the present invention are tested in acute and chronic feeding assays essentially as described above.
  • the compounds are found to significantly reduce 24 h food intake, which effect is blocked by pre-administration of the 5-HT 2C receptor antagonist.
  • the compounds also are found to dose-dependently reduce RQ without significantly changing the energy expenditure during the light photo-period.
  • the compounds are found to reduce caloric intake and increase the proportion of fuel deriving from fat utilization, without significantly changing the resting metabolic rate.
  • the compounds are found to significantly decrease cumulative food intake and cumulative body weight change in a dose-dependent manner compared to control animals. The decrease in body weight is found to be due to loss of adipose tissue while lean body mass is not changed.
  • Marble burying in mice has been used to model anxiety disorders including obsessive-compulsive disorders (OCD) due to ethological study of the behavior (e.g. Gyertyan I. "Analysis of the marble burying response: Marbles serve to measure digging rather than evoke burying", Behavioural Pharmacology 6: 24-31, (1995 )) and due to the pharmacological effects of clinical standards (c.f., Njung'E K. Handley SL. "Evaluation of marble-burying behavior as a model of anxiety", Pharmacology, Biochemistry & Behavior. 38: 63-67, (1991 )); Borsini F., Podhoma J., and Marazziti, D.
  • OCD obsessive-compulsive disorders
  • drugs used in the treatment of generalized anxiety in humans e.g. benzodiazepines
  • compounds used to treat OCD e.g. SSRIs like fluoxetine
  • mice House experimentally-na ⁇ ve male, NIH Swiss mice (Harlan Sprague-Dawley, Indianapolis, IN) weighing between 28-35 g in groups of 12 for at least three days prior to testing in a vivarium with 12 h light and dark cycles. Conduct experiments during the light cycle in a dimly lit experimental testing room. Dose mice with vehicle or test compound and, after a specified pretreatment interval (generally 30 min.), place each mouse individually on a rotorod (Ugo Basile 7650) operating at a speed of 6 revolutions/min. and observe for falling. After 2 min.
  • a rotorod Ugo Basile 7650
  • mice on the rotorod, place the mice individually in a 17 x 28 x 12 cm high plastic tub with 5 mm sawdust shavings on the floor that are covered with 20 blue marbles (1.5 cm diameter) placed in the center. After 30 min., count the number of marbles buried (2/3 covered with sawdust). Assess the test compound's effect on marble burying with Dunnett's test and the effect on rotorod performance by Fisher's exact test.
  • Representative compounds of the present invention are assayed in the marble burying assay essentially as described and are surprisingly found to reduce burying behavior in the test mice. The reduction of burying behavior is found to be blocked by co-administration of the 5-HT 2C antagonist.
  • the anxiolytic compound chlordiazepoxide and the antipsychotic compound chlorpromazine decrease marble burying only at doses that also disrupt rotorod performance.
  • mice naturally will construct nests of material available in their living environment. Since this behavior is obsessive in nature, it has been used to model OCD ( Xia Li, Denise Morrow and Jeffrey M. Witkin, "Decreases in nestlet shredding of mice by serotonin uptake inhibitors: comparison with marble burying", Psychopharmacology, submitted July 14, 2003 ). House experimentally-na ⁇ ve male, NIH Swiss mice (Harlan Sprague-Dawley, Indianapolis, IN) weighing between 28-35 g in groups of 12 for at least three days prior to testing in a vivarium with a 12 h light/dark cycle. Conduct experiments during the light cycle in an experimental room with normal overhead fluorescent lighting.
  • mice with vehicle or test compound and after a specified pretreatment interval place the mice individually in a 17 x 28 x 12 cm high plastic tub with about 5 mm sawdust shavings on the floor along with a pre-weighed multi-ply gauze pad (51 mm square). After 30 min., weigh the remainder of the gauze pad not removed by the mouse. Determine the weight of the gauze used for nestlet construction by subtraction. Compare the results for test compound treated mice to the results for vehicle control treated mice with Dunnett's test.
  • Clinically effective OCD treatment standard compounds suppress nestlet shredding at doses that are devoid of motor-impairing effects as measured by the rotorod test.
  • the in vivo efficacy of 5HT 2C compounds at the 5HT 2C receptor is confirmed by the prevention of effects of the 5HT 2C agonists on nestlet shredding by co-administration of the 5HT 2C receptor antagonist, 6-chloro-5-methyl-N- ⁇ 2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbonyl ⁇ -2,3-dihydroindole.
  • Representative compounds of the present invention are assayed essentially as described above and are surprisingly found to suppress nestlet shredding at doses that are devoid of motor-impairing effects as measured by the rotorod test.
  • the anxiolytic chlordiazepoxide and the psychomotor stimulant d -amphetamine decreases nestlet shredding only at doses that produce motoric side effects (depression or stimulation, respectively).
  • the behavioral testing chamber is also equipped with a water bottle that is weighed before and after the session to determine the amount of water consumed.
  • Clinically effective OCD treatment standard compounds e.g. chlomipramine, fluoxetine
  • the in vivo efficacy of 5HT 2C compounds at the 5HT 2C receptor is confirmed by the prevention of effects of the 5HT 2C agonists on excessive drinking by co-administration of the 5HT 2C receptor antagonist, 6-chloro-5-methyl-N- ⁇ 2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbonyl ⁇ -2,3-dihydroindole.
  • Representative compounds of the present invention are assayed in the schedule-induced polydipsia assay essentially as described above and are surprisingly found to suppress schedule-induced polydipsia without producing notable changes in motor patterns, food intake, or behavior the following day. The behavior suppression is blocked by co-administration of the 5-HT 2C antagonist.
  • the psychomotor stimulant d -amphetamine decreases excessive drinking only at behaviorally stimulating doses and these effects are not prevented by the 5HT 2C receptor antagonist.
  • compositions comprising a pharmaceutically acceptable excipient and at least one compound of Formula I or a pharmaceutically acceptable salt thereof.
  • These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g. REMINGTON'S PHARMACEUTICAL SCIENCES, (16h ed. 1980 ).
  • the active ingredient is usually mixed with at least one excipient, diluted by at least one excipient, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compounds are generally effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.01 to about 30 mg/kg.
  • the range of about 0.1 to about 15 mg/kg/day, in single or divided dose is especially preferred.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g. , U.S. Patent 5,023,252, issued June 11, 1991 , herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • a drug delivery catheter used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent 5,011,472, issued April 30, 1991 , which is herein incorporated by reference.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compound employed, the type of pharmacokinetic profile desired from the route of administration, and the state of the patient.

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Claims (11)

  1. Verbindung der Formel I
    Figure imgb0093
     worin
    R6 für -(C1-C3)-Alkyl-S-(C0-C3)-alkyl-R10, -(C1-C3)-Alkyl-NR12-(C0-C3)-alkyl-R11 oder -(C1-C3)-Alkyl-O-(C0-C3)-alkyl-R11 steht,
    R10 steht für
    a) einen aromatischen heterocyclischen Substituenten, der ausgewählt ist aus der Gruppe, die besteht aus Tetrazolyl, 1,2,3-Thiadiazolyl, 1,3,4-Thiadiazolyl, 1,2,4-Thiadiazolyl, 1,2,3-Oxadiazolyl, 1,3,4-Oxadiazolyl und 1,2,4-Oxadiazolyl, wobei jede dieser Gruppen optional substituiert sein kann mit einem Substituenten, der ausgewählt ist aus der Gruppe, die besteht aus (C1-C4)-Alkyl, das optional substituiert ist mit 1 bis 5 Fluorsubstituenten, Ph1-(C0-C3)-Alkyl, Ar1-(C0-C3)-Alkyl, (C1-C4)-Alkyl-C(O)-, Ph1-(C0-C3)-Alkyl-C(O)-, Ar1-(C0-C3)-Alkyl-C(O)-, (C1-C4)-Alkyl-NR12-(C0-C3)-alkyl, mit optionaler Substitution an der (C1-C4)-Alkylgruppe mit 1 bis 5 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NR12-(C0-C3)-alkyl, Ph1-(C0-C3)-Alkyl-NR12-(C0-C3)-alkyl, Ar1-(C0-C3)-Alkyl-NR12-(C0-C3)-alkyl,
    b) einen aromatischen heterocyclischen Substituenten, der ausgewählt ist aus der Gruppe, die besteht aus Imidazolyl, Thiazolyl, Isothiazolyl, Thiophenyl, Pyrazolyl, Oxazolyl, Isoxazolyl, 1,2,3-Triazolyl, 1,2,4-Triazolyl oder einem Heterocyclyl, das ausgewählt ist aus Thiazolinyl, wobei jede dieser Gruppen optional substituiert sein kann mit ein bis zwei Substituenten, die ausgewählt sind aus der Gruppe, die besteht aus (C1-C6)-Alkyl, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, Ph1-(C0-C3)-Alkyl, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, Ar1-(C0-C3)-Alkyl, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkyl-C(O)-, Ph1-(C0-C3)-Alkyl-C(O)-, Ar1-(C0-C3)-Alkyl-C(O)-, (C1-C6)-Alkyl-NH-C(O)-, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, Ph1-(C0-C3)-Alkyl-NH-C(O)-, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, und Ar1-(C0-C3)-Alkyl-NH-C(O)-, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten,
    oder optionaler Substitution an den Ringkohlenstoffatomen mit ein oder zwei Substituenten, die ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, (C1-C6)-Alkyl-CH=CH-, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkoxy, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkylthio, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, Ph1-(C0-C3)-Alkylthio, (C1-C6)-Alkyl-NR12-(C0-C3)-alkyl-, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NR12-(C0-C3)-alkyl, Ph1-(C0-C3)-Alkyl-NR12-(C0-C3)-alkyl-, Ar1-(C0-C3)-Alkyl-NR12-(C0-C3)-alkyl-, Het1-(C0-C3)-Alkyl-, (C1-C6)-Alkyl-C(O)-NH-, Ph1-(C0-C3)-Alkyl-C(O)-NH-, Ar1-(C0-C3)-Alkyl-C(O)-NH-, (C1-C6)-Alkyl-O-C(O)-NH-, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, Ph1-(C0-C3)-Alkyl-O-C(O)-NH-, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, und Ar1-(C0-C3)-Alkyl-O-C(O)-NH-, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, oder mit optionaler Substitution an zwei benachbarten Ringatomen mit einem bivalenten 3 bis 4 Kohlenwasserstoffsubstituenten, der zusammen mit den Ringatomen, an die er gebunden ist, einen Benzolring oder einen partial gesättigten fünf- oder sechsgliedrigen Ring bildet,
    c) Phenyl, das optional substituiert ist mit
    i) 1 bis 5 Substituenten, die unabhängig ausgewählt sind aus Halogen, oder
    ii) 1 bis 3 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, -SCF3, Nitro, Hydroxy, (C1-C6)-Alkyl, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, und (C1-C6)-Alkoxy, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, oder
    iii) 0, 1 oder 2 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, -SCF3, Methyl, -CF3, Methoxy, -OCF3, Nitro und Hydroxy, zusammen mit einem Substituenten, der ausgewählt ist aus der Gruppe, die besteht aus (C3-C7)-Cycloalkyl-(C0-C5)-alkyl, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten und das optional an der Cycloalkylgruppe und unabhängig substituiert ist mit 1 bis 6 Substituenten, die ausgewählt sind aus Fluor und Methyl, mit der Maßgabe, dass nicht mehr als 2 Substituenten für Methyl stehen, Ph1-(C0-C5)-Alkyl, Ar1-(C0-C5)-Alkyl, Thiazolyl-(C0-C1)-alkyl, das optional substituiert ist mit einem Substituenten, der unabhängig ausgewählt ist aus der Gruppe, die besteht aus Halogen, (C1-C6)-Alkyl, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkyl-NR12-(C0-C3)-alkyl-, das an der (C1-C6)-Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten, und (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NR12-(C0-C3)-alkyl, (C1-C6)-Alkyl-CH=CH-, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-CH=CH-, das optional am Alkyl substituiert ist mit 1 bis 6 Fluorsubstituenten, und das an der Cycloalkylgruppe optional und unabhängig substituiert ist mit 1 bis 6 Substituenten, die ausgewählt sind aus Fluor und Methyl, mit der Maßgabe, dass nicht mehr als 2 Substituenten für Methyl stehen, (C1-C6)-Alkyl-S-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-S-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-S-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-S-(C0-C5)-alkyl, (C1-C6)-Alkyl-O-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-O-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-O-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-O-(C0-C5)-alkyl, (C1-C6)-Alkyl-SO2-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-SO2-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-SO2-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-SO2-(C0-C5)-alkyl, (C1-C6)-Alkyl-C(O)-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-C(O)-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-C(O)-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-C(O)-(C0-C5)-alkyl, (C1-C6)-Alkyl-NH-(C0-C5)-alkyl , das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NH-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-NH-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-NH-(C0-C5)-alkyl, Het1-(C0-C3)-Alkyl-, (C1-C6)-Alkyl-NH-C(O)-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NH-C(O)-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-NH-C(O)-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-NH-C(O)-(C0-C5)-alkyl, (C1-C6)-Alkyl-(C0-C3)-alkyl-C(O)-NH-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-C(O)-NH-(C0-C5)-alkyl , Ph1-(C0-C3)-Alkyl-C(O)-NH-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-C(O)-NH-(C0-C5)-alkyl, (C1-C6)-Alkyl-NH-SO2-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkly-NH-SO2-(C0-C5)-alkyl, (C1-C6)-Alkyl-SO2-NH-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-SO2-NH-(C0-C5)-alkyl,
    d) einen aromatischen heterocyclischen Substituenten, der ausgewählt ist aus der Gruppe, die besteht aus Pyridyl, Pyridazinyl, Pyrimidinyl, Pyrazinyl, wobei jede dieser Gruppen optional substituiert sein kann mit ein oder zwei Substituenten, die unabhängig aus der Gruppe ausgewählt sind, die besteht aus Halogen, Cyano, -SCF3, Methyl, -CF3, Methoxy, -OCF3, Nitro, Hydroxy, und wobei diese Gruppe optional weiter substituiert sein kann mit einem Substituenten, der ausgewählt ist aus der Gruppe, die besteht aus (C3-C7)-Cycloalkyl-(C0-C5)-alkyl, das optional an der Alkylgruppe weiter substituiert sein kann mit 1 bis 6 Fluorsubstituenten, und das an der Cycloalkylgruppe optional substituiert sein kann mit 1 bis 6 Substituenten, die ausgewählt sind aus Fluor und Methyl, mit der Maßgabe, dass nicht mehr als 2 Substituenten für Methyl stehen, Ph1-(C0-C5)-Alkyl, Ar1-(C0-C5)-Alkyl, Thiazolyl-(C0-C1)-alkyl, das optional substituiert ist mit einem Substituenten, der unabhängig ausgewählt ist aus der Gruppe, die besteht aus Halogen, (C1-C6)-Alkyl, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkyl-NR12-(C0-C3)-alkyl, das an der (C1-C6)-Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten, und (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NR12-(C0-C3)-alkyl, (C1-C6)-Alkyl-CH=CH-, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-CH=CH-, das an der Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten und das an der Cycloalkylgruppe optional und unabhängig substituiert ist mit 1 bis 6 Substituenten, die ausgewählt sind aus Fluor und Methyl, mit der Maßgabe, dass nicht mehr als 2 Substituenten für Methyl stehen, (C1-C6)-Alkyl-S-(C0-C5)-alkyl, das an der (C1-C6)-Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-S-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-S-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-S-(C0-C5)-alkyl, (C1-C6)-Alkyl-O-(C0-C5)-alkyl, das an der (C1-C6)-Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-O-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-O-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-O-(C0-C5)-alkyl, (C1-C6)-Alkyl-SO2-(C0-C3)-alkyl, das an der (C1-C6)-Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-SO2-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-SO2-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-SO2-(C0-C5)-alkyl, (C1-C6)-Alkyl-C(O)-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-C(O)-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-C(O)-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-C(O)-(C0-C5)-alkyl, (C1-C6)-Alkyl-NH-(C0-C5)-alkyl, das an der (C1-C6)-Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NH-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-NH-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-NH-(C0-C5)-alkyl, Het1-(C0-C5)-Alkyl-, (C1-C6)-Alkyl-NH-C(O)-(C0-C5)-alkyl, das an der (C1-C6)-Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NH-C(O)-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-NH-C(O)-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-NH-C(O)-(C0-C5)-alkyl, (C1-C6)-Alkyl-C(O)-NH-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-C(O)-NH-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-C(O)-NH-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-C(O)-NH-(C0-C5)-alkyl, oder
    e) alpha-Naphthalyl, Chinolin-2-yl, Chinolin-3-yl oder Chinolin-4-yl,
    R11 steht für a) Phenyl, das optional substituiert ist mit
    i) 1 bis 5 Substituenten, die unabhängig ausgewählt sind aus Halogen, oder
    ii) 1 bis 3 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, Methyl, -CF3, -SCF3, Methoxy, Nitro und Hydroxy, oder
    iii) 0, 1 oder 2 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, Methyl, -CF3, -SCF3, Methoxy, Nitro und Hydroxy, und die weiter substituiert sind mit einem Substituenten, der ausgewählt ist aus der Gruppe, die besteht aus (C1-C6)-Alkyl, das optional weiter substituiert mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkyl-O-(C0-C5)-alkyl, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkyl-CH=CH-, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-CH=CH-, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, und das an der Cycloalkylgruppe optional substituiert ist mit 1 bis 6 Substituenten, die ausgewählt sind aus Fluor und Methyl, mit der Maßgabe, dass nicht mehr als 2 Substituenten für Methyl stehen, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-O-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-O-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-O-(C0-C5)-alkyl, (C1-C6)-Alkyl-S-(C0-C5)-alkyl, das an der (C1-C6)-Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-S-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-S-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-S-(C0-C5)-alkyl, (C1-C6)-Alkyl-SO2-(C0-C5)-alkyl, das optional substituiert ist an der (C1-C6)-Alkyl-gruppe mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-SO2-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-SO2-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-SO2-(C0-C5)-alkyl, (C1-C6)-Alkyl-C(O)-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-C(O)-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-C(O)-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-C(O)-(C0-C5)-alkyl, (C1-C6)-Alkyl-NH-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NH-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-NH-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-NH-(C0-C5)-alkyl, (C1-C6)-Alkyl-NH-C(O)-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NH-C(O)-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-NH-C(O)-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-NH-C(O)-(C0-C5)-alkyl, Het1-(C0-C5)-Alkyl-, (C1-C6)-Alkyl-C(O)-NH-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-(C0-C5)-alkyl-C(O)-NH-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-C(O)-NH-(C0-C5)-alkyl, und Ar1-(C0-C3)-Alkyl-C(O)-NH-(C0-C5)-alkyl,
    b) Pyridyl, das optional substituiert ist mit
    i) 1 bis 3 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, Methyl, -CF3, -SCF3, Methoxy, Nitro und Hydroxy, oder
    ii) 0, 1 oder 2 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, Methyl, -CF3, -SCF3, Methoxy, Nitro und Hydroxy, und die ferner substituiert sind mit einem Substituenten, der ausgewählt ist aus der Gruppe, die besteht aus (C1-C6)-Alkyl, das optional weiter substituiert mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkyl-O-(C0-C5)-alkyl, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkyl-CH=CH-, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-CH=CH-, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, und an der Cycloalkylgruppe optional substituiert ist mit 1 bis 6 Substituenten, die ausgewählt sind aus Fluor und Methyl, mit der Maßgabe, dass nicht mehr als 2 Substituenten für Methyl stehen, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-O-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-O-(C0-C5)-alkyl, (C1-C6)-Alkyl-S-(C0-C5)-alkyl, das an der (C1-C6)-Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-S-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-S-(C0-C5)-alkyl, (C1-C6)-Alkyl-SO2-(C0-C5)-alkyl, das optional substituiert ist an der (C1-C6)-Alkyl-gruppe mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-SO2-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-SO2-(C0-C5)-alkyl, (C1-C6)-Alkyl-C(O)-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-C(O)-(C0-C3)-alkyl, Ph1-(C0-C3)-Alkyl-C(O)-(C0-C5)-alkyl, (C1-C6)-Alkyl-NH-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NH-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-NH-(C0-C5)-alkyl, (C1-C6)-Alkyl-NH-C(O)-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NH-C(O)-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-NH-C(O)-(C0-C5)-alkyl, (C1-C6)-Alkyl-C(O)-NH-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-(C0-C5)-alkyl-C(O)-NH-(C0-C5)-alkyl, und Ph1-(C0-C3)-Alkyl-C(O)-NH-(C0-C5)-alkyl,
    c) Pyridazinyl, das optional substituiert ist mit 1 oder 2 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, Hydroxy, (C1-C6)-Alkyl, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkoxy, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, und (C1-C6)-Alkylthio, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, oder
    d) ein fünfgliedriges aromatisches Heterocyclyl, das ausgewählt ist aus der Gruppe Thiophenyl, Thiazol, Isothiazol, mit optionaler Substitution mit 1 oder 2 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, Hydroxy, (C1-C6)-Alkyl, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkoxy, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkylthio, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkylamino, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, und (C1-C6)-Alkyl-C(O)-,
    R12 für Wasserstoff oder Methyl steht, R13 steht für
    a) Phenyl, das optional substituiert ist mit
    i) 1 bis 5 Substituenten, die unabhängig ausgewählt sind aus Halogen, oder
    ii) 1 bis 3 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, -SCF3, Nitro, Hydroxy, (C1-C6)-Alkyl, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, und (C1-C6)-Alkoxy, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, oder
    iii) 0, 1 oder 2 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, -SCF3, Methyl, -CF3, Methoxy, -OCF3, Nitro und Hydroxy, zusammen mit einem Substituenten, der ausgewählt ist aus der Gruppe, die besteht aus (C3-C7)-Cycloalkyl-(C0-C5)-alkyl, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten und das an der Cycloalkylgruppe optional und unabhängig substituiert ist mit 1 bis 6 Substituenten, die ausgewählt sind aus Fluor und Methyl, mit der Maßgabe, dass nicht mehr als 2 Substituenten für Methyl stehen, Ph1-(C0-C5)-Alkyl, Ar1-(C0-C5)-Alkyl, (C1-C6)-Alkyl-CH=CH-, das optional substituiert mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C5)-alkyl-CH=CH-, das an der Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten und das an der Cycloalkylgruppe optional und unabhängig substituiert ist mit 1 bis 6 Substituenten, die ausgewählt sind aus Fluor und Methyl, mit der Maßgabe, dass nicht mehr als 2 Substituenten für Methyl stehen, (C1-C6)-Alkyl-S-(C0-C5)-alkyl, das an der (C1-C6)-Alkylgruppe optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycoalkyl-(C0-C3)-alkyl-S-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-S-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-S-(C0-C5)-alkyl, (C1-C6)-Alkyl-O-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-O-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-O-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-O-(C0-C5)-alkyl, (C1-C6)-Alkyl-SO2-(C0-C5)-alkyl, das optional substituiert ist an der (C1-C6)-Alkyl-gruppe mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-SO2-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-SO2-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-SO2-(C0-C5)-alkyl, (C1-C6)-Alkyl-C(O)-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-C(O)-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-C(O)-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-C(O)-(C0-C5)-alkyl, (C1-C6)-Alkyl-NH-(C0-C5)-alkyl, das optional substituiert ist an der (C1-C6)-Alkyl-gruppe mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyll-NH-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-NH-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-NH-(C0-C5)-alkyl, Het1-(C0-C3)-Alkyl-, (C1-C6)-Alkyl-NH-C(O)-(C0-C5)-alkyl, das optional an der (C1-C6)-Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NH-C(O)-(C0-C5)-alkyl, Ph1-(C0-C3)-Alkyl-NH-C(O)-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-NH-C(O)-(C0-C5)-alkyl, (C1-C6)-Alkyl-(C0-C3)-alkyl-C(O)-NH-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-C(O)-NH-(C0-C5)-alkyl , Ph1-(C0-C3)-Alkyl-C(O)-NH-(C0-C5)-alkyl, Ar1-(C0-C3)-Alkyl-C(O)-NH-(C0-C5)-alkyl, (C1-C6)-Alkyl-NH-SO2-(C0-C5)-alkyl, das optional substituiert ist an der (C1-C6)-Alkylgruppe mit1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NH-SO2-(C0-C5)-alkyl, (C1-C6)-Alkyl-SO2-NH-(C0-C5)-alkyl, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-SO2-NH-(C0-C5)-alkyl, oder
    b) Thiophenyl, das der Gruppe, die Halogen, optional substituiert ist mit ein oder zwei Substituenten, die ausgewählt sind aus besteht aus Cyano, (C1-C6)-Alkyl, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, Ph1-(C0-C3)-Alkyl, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, Ar1-(C0-C3)-Alkyl, das optional an der Alkylgruppe substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkyl-C(O)-, Ph1-(C0-C3)-Alkyl-C(O)-, Ar1-(C0-C3)-Alkyl-C(O)-, (C1-C6)-Alkyl-NH-C(O)-, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, Ph1-(C0-C3)-Alkyl-NH-C(O)-, das optional substituiert ist an der Alkylgruppe mit 1 bis 6 Fluorsubstituenten, Ar1-(C0-C3)-Alkyl-NH-C(O)-, das optional substituiert ist an der Alkylgruppe mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkyl-CH=CH-, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkoxy, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, (C1-C6)-Alkylthio, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, Ph1-(C0-C3)-Alkylthio, (C1-C6)-Alkyl-NR12-(C0-C3)-alkyl-, das optional substituiert ist an der (C1-C6)-Alkylgruppe mit 1 bis 6 Fluorsubstituenten, (C3-C7)-Cycloalkyl-(C0-C3)-alkyl-NR12-(C0-C3)-alkyl, Ph1-(C0-C3)-Alkyl-NR12-(C0-C3)-alkyl-, Ar1-(C0-C3)-Alkyl-NR12-(C0-C3)-alkyl-, Het1-(C0-C3)-Alkyl-, (C1-C6)-Alkyl-C(O)-NH-, Ph1-(C0-C3)-Alkyl-C(O)-NH-, Ar1-(C0-C3)-Alkyl-C(O)-N H-, (C1-C6)-Alkyl-O-C(O)-NH-, das optional substituiert ist mit 1 bis 6 Fluorsubstituenten, Ph1-(C0-C3)-Alkyl-O-C(O)-NH-, das optional substituiert ist an der Alkylgruppe mit 1 bis 6 Fluorsubstituenten, und Ar1-(C0-C3)-Alkyl-O-C(O)-NH-, das optional substituiert ist an der Alkylgruppe mit 1 bis 6 Fluorsubstituenten,
    Ar1 für Pyridyl steht, das optional substituiert ist mit 1 bis 4 unabhängig ausgewählten Halogensubstituenten, oder mit 1 bis 3 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, Hydroxy, Acetyl, Methyl, -CF3, Methoxy, -OCF3, Methylthio, -SCF3,
    Ph1 für Phenyl steht, das optional und unabhängig substituiert ist mit 1 bis 5 Halogensubstituenten, oder mit 1 bis 3 Substituenten, die unabhängig ausgewählt sind aus der Gruppe, die besteht aus Halogen, Cyano, Hydroxy, Acetyl, Methylthio, -SCF3, (C1-C6)-Alkyl, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten, und (C1-C6)-Alkoxy, das optional weiter substituiert ist mit 1 bis 6 Fluorsubstituenten,
    Het1 für ein gesättigtes, Stickstoff-enthaltendes Heterocyclyl steht, das ausgewählt ist aus der Gruppe, die besteht aus Pyrrolidinyl, Piperidinyl, Homopiperidinyl, Morpholinyl, Thiomorpholinyl, Homomorpholinyl und Homothiomorpholinyl, wobei jede dieser Gruppen optional substituiert sein kann mit einer (C1-C6)-Alkylgruppe oder mit zwei Methylsubstituenten, oder ein pharmazeutisch akzeptables Salz hiervon.
  2. Verbindung nach Anspruch 1 der Formel (Ia)
    Figure imgb0094
     worin
    R10 wie in der Formel (I) von Anspruch 1 definiert ist,
    oder ein pharmazeutisch akzeptables Salz hiervon.
  3. Verbindung nach Anspruch 1 der Formel (Ib)
    Figure imgb0095
     worin
    R11 wie in der Formel (I) von Anspruch 1 definiert ist,
    oder ein pharmazeutisch akzeptables Salz hiervon.
  4. Verbindung nach Anspruch 1 der Formel (Ic)
    Figure imgb0096
     worin
    R13 wie in der Formel (I) von Anspruch 1 definiert ist,
    oder ein pharmazeutisch akzeptables Salz hiervon.
  5. Pharmazeutische Zusammensetzung, umfassend eine Verbindung nach einem der Ansprüche 1 bis 4, oder ein pharmazeutisch akzeptables Salz hiervon, als Wirkstoff in Assoziation mit einem pharmazeutisch akzeptablen Träger, Verdünnungsmittel oder Hilfsstoff.
  6. Verbindung nach einem der Ansprüche 1 bis 4 oder ein pharmazeutisch akzeptables Salz hiervon, für die Verwendung als ein Pharmazeutikum.
  7. Verbindung nach einem der Ansprüche 1 bis 4 oder ein pharmazeutisch akzeptables Salz hiervon für die Verwendung zur Behandlung einer Störung, die ausgewählt ist aus Obesität, Hyperphagie, obsessiver/kompulsiver Störung, Depression, Angst, Substanzmissbrauch, Schlafstörung, Hitzewallungen und/oder Hypogonadismus.
  8. Verbindung nach Anspruch 7, worin die Störung Obesität ist.
  9. Verbindung nach Anspruch 7, worin die Störung eine obsessive/kompulsive Störung ist.
  10. Verbindung nach Anspruch 7, worin die Störung eine Depression ist.
  11. Verbindung nach Anspruch 7, worin die Störung Angst ist.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2619450C (en) * 2005-09-01 2013-10-22 Eli Lilly And Company 6-n-linked heterocycle-substituted 2,3,4,5-tetrahydro-1h-benzo[d]azepines as 5-ht2c receptor agonists
ATE437859T1 (de) * 2005-09-01 2009-08-15 Lilly Co Eli 6-substituierte- 2,3,4,5-tetrahydro-1h- benzoädüazepine als 5-ht2c-rezeptoragonisten
US8158617B2 (en) 2006-05-16 2012-04-17 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and use thereof
US7897595B2 (en) 2006-05-26 2011-03-01 Forest Laboratories Holdings Limited Pyridoazepine derivatives
JP5520051B2 (ja) 2007-11-15 2014-06-11 武田薬品工業株式会社 縮合ピリジン誘導体およびその用途
US8748623B2 (en) * 2009-02-17 2014-06-10 Syntrix Biosystems, Inc. Pyridinecarboxamides as CXCR2 modulators
JP6486002B2 (ja) 2010-08-23 2019-03-20 シントリックス・バイオシステムズ・インコーポレイテッドＳｙｎｔｒｉｘ Ｂｉｏｓｙｓｔｅｍｓ， Ｉｎｃ． Ｃｘｃｒ２モジュレーターとしてのアミノピリジンカルボキサミドおよびアミノピリミジンカルボキサミド
SG188361A1 (en) * 2010-09-01 2013-04-30 Arena Pharm Inc Non-hygroscopic salts of 5-ht2c agonists
US20130267500A1 (en) 2010-09-01 2013-10-10 Arena Pharmaceuticals, Inc. 5-ht2c receptor agonists in the treatment of disorders ameliorated by reduction of norepinephrine level
CN103189358A (zh) * 2010-09-01 2013-07-03 艾尼纳制药公司 5-ht2c激动剂的快速溶解剂型
JP2013539470A (ja) * 2010-09-01 2013-10-24 アリーナ ファーマシューティカルズ， インコーポレイテッド ロルカセリンと光学活性な酸との塩
WO2015066344A1 (en) 2013-11-01 2015-05-07 Arena Pharmaceuticals, Inc. 5-ht2c receptor agonists and compositions and methods of use
CN105622511B (zh) * 2014-11-03 2018-01-23 北京瑞都医药科技有限公司 一种减肥药物及其制备方法
JPWO2019131902A1 (ja) 2017-12-27 2020-12-10 武田薬品工業株式会社 腹圧性尿失禁および便失禁の治療薬

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4265890A (en) * 1978-07-07 1981-05-05 Smithkline Corporation 6-Phenyl thio- and 6-cyclohexyl thio-2,3,4,5-tetrahydro-1H-3-benzazepines
EP0285287A3 (de) 1987-03-23 1990-08-16 Smithkline Beecham Corporation Verwendung von 3-Benzazepinen zur Behandlung von gastrointestinalen Mobilitätsstörungen
US4985352A (en) * 1988-02-29 1991-01-15 The Trustees Of Columbia University In The City Of New York DNA encoding serotonin 1C (5HT1c) receptor, isolated 5HT1c receptor, mammalian cells expressing same and uses thereof
GB9116824D0 (en) 1991-08-05 1991-09-18 Smithkline Beecham Corp Chemical compounds
US5639748A (en) * 1991-08-05 1997-06-17 Smithkline Beecham Corporation 6,9-disubstituted benzazepines having α-adrenoceptor blocking activity
WO1993004866A1 (en) * 1991-09-11 1993-03-18 Canon Kabushiki Kaisha Improved cleaning member for ink jet head and ink jet device provided with said cleaning member
GB9119467D0 (en) 1991-09-12 1991-10-23 Smithkline Beecham Corp Chemical compounds
US5698766A (en) * 1995-04-05 1997-12-16 The Regents Of The University Of California Transgenic animal model for testing drugs for treating eating disorders and epilepsy
EP1213017A3 (de) 2000-12-05 2003-11-12 Akzo Nobel N.V. Verwendung von einem 5-HT2C Rezeptor Agonist zur Behandlung von Hitzewallungen
JPWO2002074746A1 (ja) * 2001-03-16 2004-07-08 山之内製薬株式会社 ベンゾアゼピン誘導体
DE60206762T2 (de) 2001-07-13 2006-07-13 Pharmacia & Upjohn Co. Llc, Kalamazoo Hexahydroazepino(4,5-g)indole und -indoline als 5-ht rezeptor-liganden
CA2468010A1 (en) * 2001-11-28 2003-06-05 Pharmacia & Upjohn Company Benzazepine derivatives and their use as 5-ht ligands
US6953787B2 (en) * 2002-04-12 2005-10-11 Arena Pharmaceuticals, Inc. 5HT2C receptor modulators
CN1805938B (zh) * 2003-06-17 2010-06-16 艾尼纳制药公司 用于治疗5ht2c受体相关疾病的苯并氮杂卓衍生物
EP1636191A2 (de) 2003-06-17 2006-03-22 Arena Pharmaceuticals, Inc. Für die behandlung von mit dem 5ht2c rezeptor assoziierten krankheiten geeignete benzazepinderivative
TW200510324A (en) * 2003-08-11 2005-03-16 Lilly Co Eli 6-(2,2,2-trifluoroethylamino)-7-chiloro-2, 3, 4, 5-tetrahydro-1h-benzo[d]azepine as a 5-ht2c receptor agonist
US20080009478A1 (en) 2003-10-22 2008-01-10 Arena Pharmaceuticals, Inc. Benzazepine Derivatives and Methods of Prophylaxis or Treatment of 5Ht2c Receptor Associated Diseases
US20070275949A1 (en) 2003-10-22 2007-11-29 Arena Pharmaceuticals, Inc. Benzazepine Derivatives and Methods of Prophylaxis or Treatment of 5Ht2C Receptor Associated Diseases
AU2005217602B2 (en) * 2004-02-25 2011-02-17 Eli Lilly And Company 6-substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepines as 5-HT2C receptor agonists
NZ555981A (en) 2004-12-21 2011-01-28 Arena Pharm Inc Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
EP1833473B1 (de) 2004-12-23 2009-09-09 Arena Pharmaceuticals, Inc. 5ht2c-rezeptor-modulator-zusammensetzungen und anwendungsverfahren
ATE437859T1 (de) * 2005-09-01 2009-08-15 Lilly Co Eli 6-substituierte- 2,3,4,5-tetrahydro-1h- benzoädüazepine als 5-ht2c-rezeptoragonisten

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
EP3610890A1 (de) 2012-11-14 2020-02-19 The Johns Hopkins University Verfahren und zusammensetzungen zur behandlung von schizophrenie

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ES2328520T3 (es) 2009-11-13
JP2009508818A (ja) 2009-03-05
CY1110531T1 (el) 2015-04-29
CA2619566A1 (en) 2007-03-08
SI1924560T1 (sl) 2010-01-29
JP5165568B2 (ja) 2013-03-21
DE602006008323D1 (de) 2009-09-17
DK1924560T3 (da) 2009-10-19
PL1924560T3 (pl) 2009-12-31
EP1924560A1 (de) 2008-05-28
ATE438627T1 (de) 2009-08-15
WO2007028082A1 (en) 2007-03-08
PT1924560E (pt) 2009-10-23
CA2619566C (en) 2013-08-13
US20080255092A1 (en) 2008-10-16
US7994163B2 (en) 2011-08-09

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